Interventional options for the management of refractory cancer pain--what is the evidence?

PURPOSE: Pain is the most common symptom in cancer patients. Standard pain treatment according to the WHO three-step analgesic ladder provides effective pain management in approximately 70-90% of cancer patients. Refractory pain is defined as not responding to "standard" treatments. Interventional analgesic techniques can be used in an attempt to control refractory pain in patients in whom conventional analgesic strategies fail to provide effective pain relief or are intolerable due to severe adverse effects. This systematic review aims to provide the latest evidence on interventional refractory pain management in cancer patients. METHODS: Systematic literature search in Cochrane, EMBASE and PubMed including reviews and randomised controlled trials (RCTs) and non-randomised controlled trials in the absence of reviews. RESULTS: Neuraxial analgesia may play a role in refractory cancer pain management. Paravertebral blocks decrease the incidence of persistent post-surgical pain after breast cancer. Coeliac plexus blocks improve pain scores in refractory pancreatic cancer pain for up to 4 weeks after the intervention with fewer burdensome side effects as compared to opioids. Cordotomy has mainly been studied in mesothelioma, and the case series suggest possible benefit for pain at the expense of a relatively high risk of side effects. CONCLUSIONS: Overall, very few RCTs have been conducted on interventional pain techniques. In reality, it is very difficult to undertake large controlled trials for a number of reasons. Therefore, today's best evidence for practice may be from large case series of comparable patients with careful response and toxicity evaluation and follow-up.

Therapeutic challenges in cancer pain management: a systematic review of methadone.

The proven therapeutic efficacy of methadone in cancer pain is hindered by a challenging pharmacokinetic-pharmacodynamic profile, considerable interpatient variation, and increasing concern about the complexities of dosing. The objective of this study was to assess the evidence for the use of methadone in cancer pain management. The authors conducted a systematic literature search for randomized controlled trials (RCTs) published post the 2007 Cochrane review of methadone in cancer pain. Trial quality was assessed using the Oxford Quality Scoring System and Cochrane Handbook for Systematic Reviews of Interventions. Of the 152 abstracts found, 4 were RCTs (272 participants). Two RCTs compared the efficacy and safety of methadone with placebo or active control and two investigated rotation to methadone from other opioids. The studies used different routes of administration, dosing, initiation, and titration of methadone and distinct pain scoring tools and did not address the issues raised by the Cochrane review. Methadone has an important role in the management of cancer pain, with many advantages including low cost, high oral bioavailability, rapid onset of action, once-daily dosing, and postulated benefits in difficult pain control scenarios. However, due to limited research in this area, methadone dosing remains a challenge, with vigilant dose initiation, adjustment, and monitoring required. There is a need for further studies using standardized methodology to evaluate the optimal dosing strategy of methadone, the effect on different types of pain, and the role of pharmacokinetics and pharmacogenomics in clinical outcomes.

Morphine and breast tumor metastasis: the role of matrix-degrading enzymes.

Opioids including morphine are commonly used in pain management during and after cancer surgery but have been linked to a variety of pro- and anti-tumor effects. In the present study the effect of morphine administration on the localization and growth of breast tumor cells in lungs and the level of extracellular matrix (ECM) proteases were investigated. In a mouse syngeneic model of intravenously inoculated breast cancer cells, morphine administration led to a reduction in the localization and growth of tumors in the lungs and a reduction in circulating matrix metalloproteinase-9 (MMP-9) and urokinase-like plasminogen activator (uPA). To model the involvement of non-malignant cells of the tumor microenvironment in the changes we observed in the level of proteases, we co-cultured breast cancer cells with macrophages, endothelial cells and fibroblasts. We found a significant elevation of matrix proteases as well as matrix protease inhibitors in co-cultures of breast cancer cells with macrophages or endothelial cells. Interestingly, morphine treatment of these co-cultures reduced the level of MMP-9 and increased its endogenous inhibitor, TIMP-1, thereby altering the proteolytic profile. Morphine affected the level of enzymes in co-cultures but not in cells grown individually. This suggests that anti-tumor effects of morphine observed in our in vivo model could be mediated at least in part through modulation of paracrine communication between cancer cells and non-malignant cells in the tumor microenvironment.

Morphine use in cancer surgery.

Morphine is the core of perioperative pain management. However, when it comes to cancer surgery the possibility that this drug might affect tumor recurrence and metastasis has raised concerns. The results of two recent retrospective clinical trials indicated that regional anesthesia/analgesia might be beneficial in prostate and breast cancer surgery. It was proposed that morphine could be responsible for the higher recurrence and mortality rate observed in the general anesthesia/opioid analgesia groups. Nevertheless, the results of several other retrospective studies and one randomized prospective trial failed to confirm any advantage for regional anesthesia/analgesia over general anesthesia and opioid analgesia. Moreover laboratory data on the effect of morphine on cancer are contradictory, ranging from tumor-promoting to anti-tumor effects. Considering that surgical stress and pain promote the recurrence and spread of cancer, choosing a proper analgesic strategy is of high significance. Although the question of whether morphine causes any harm to cancer patients remains unanswered, alternative analgesic regimens could be used concomitant to or instead of morphine to limit its potential adverse effects.

Morphine and tumor growth and metastasis.

Morphine is an analgesic widely used to alleviate cancer pain. In addition, the perioperative management of pain in cancer surgery patients most often includes opioids. However, there are reports that these drugs may alter cancer recurrence or metastasis. Several mechanisms have been proposed, such as the modulation of the immune response or cellular pathways that control the survival and migratory behavior of cancer cells. The published literature, however, presents some discrepancies, with reports suggesting that opioids may either promote or prevent the spread of cancer. It is of great importance to determine whether opioids, in particular the most widely used, morphine, may increase the risk of metastasis when used in cancer surgery. This review examines the available data on the effects of morphine which influence cancer metastasis or recurrence, including immunomodulation, tumor cell aggressiveness, and angiogenesis, with special emphasis on recently published clinical and laboratory based studies. We further discuss the parameters that may explain the difference between reports on the effects of morphine on cancer.

Role of nitric oxide and prostaglandin systems in lithium modulation of acetylcholine vasodilation.

The mechanism of lithium action, an effective treatment for bipolar disease, is still unknown. The present study examined the role of nitric oxide (NO) and prostaglandin systems in lithium modulation of acetylcholine in mesenteric vascular bed of rats by cannulating superior mesenteric artery. Acetylcholine (ACh) or sodium nitroprusside was injected under constant controlled flow induced by phenylephrine; therefore, changes in perfusion pressure reflect changes in resistance. Although 0.5 mM or 1 mM lithium-pretreatment of vascular bed causes reduction in ACh-response, 1.5 mM lithium induced no changes and 2 and 2.5 mM lithium potentiated ACh-induced mesenteric vascular bed relaxation compared to control group. Pretreatment of vascular bed with L-NAME or indomethacin decreased ACh-induced relaxation in 2 concentrations of 0.5 and 2 mM of lithium. The vasorelaxation response to sodium nitroprusside, the NO donor, was not different among lithium groups (0.5 and 2 mM) and controls. In conclusion, there is a dual modulation of endothelium-dependent relaxation, including an inhibitory effect at lower dose and a stimulating effect at higher dose of lithium in rat mesenteric vascular bed. NO synthesis or cyclooxygenase inhibition decreased vasorelaxation in both lower and higher doses of lithium, suggesting a role for NO and prostaglandin in this effect.

Effect of chronic lithium administration on endothelium-dependent relaxation of rat mesenteric bed: role of nitric oxide.

The mechanism of action of lithium, an effective treatment for bipolar disease, is still unknown. In this study, the mesenteric vascular beds of control rats and rats that were chronically treated with lithium were prepared by the McGregor method, and the mesenteric vascular bed vasorelaxation responses were examined. NADPH-diaphorase histochemistry was used to determine the activity of NOS (nitric oxide synthase) in mesenteric vascular beds. We demonstrated that ACh-induced vasorelaxation increased in the mesenteric vascular bed of rats treated with lithium. Acute No-nitro-L-arginine methyl ester (L-NAME) administration in the medium blocked ACh-induced vasorelaxation in the control group more effectively than in lithium-treated rats, while the vasorelaxant response to sodium nitroprusside, a NO donor, was not different between lithium-treated and control groups. Acute aminoguanidine administration blocked ACh-induced vasorelaxation of lithium-treated rats, but had no effect in the control rats. Furthermore, NOS activity, determined by NADPH-diaphorase staining, was significantly greater in the mesenteric vascular beds from chronic lithium-treated rats than in those from control rats. These data suggest that the enhanced ACh-induced endothelium-derived vasorelaxation in rat mesenteric bed from chronic lithium-treated rats might be associated with increased NOS activity, likely via iNOS. Simultaneous acute L-NAME and indomethacin administration suggests the possible upregulation of EDHF (endothelium-derived hyperpolarizing factor) in lithium-treated rats.